Warfarin is a widely used anticoagulant in the treatment and prevention of thrombosis, in the treatment for chronic atrial fibrillation, mechanical valves, pulmonary embolism, and dilated cardiomyopathy. It is tasteless and colorless, was used as a poison, and is still marketed as a pesticide against rats and mice. Several long-acting warfarin derivatives—superwarfarin anticoagulants—such as brodifacoum, diphenadione, chlorophacinone, bromadiolone, are used as pesticides and can produce profound and prolonged anticoagulation. Several factors increase the risk of warfarin toxicity. However, polymorphisms in cytochrome P450 genes and drug interactions account for most of the risk for toxicity complications. Each person is unique in their degree of susceptibility to toxic agents. The toxicity interpretation and the health risk of most toxic substances are a subject of uncertainty. Genetically determined low metabolic capacity in an individual can dramatically alter the toxin and metabolite levels from those normally expected, which is crucial for drugs with a narrow therapeutic index, like warfarin. Personalized approaches in interpretation have the potential to remove some of the scientific uncertainties in toxicity?cases.
References
[1]
Makris, M.; Watson, H.G. The management of coumarin-induced over-anticoagulation Annotation. Br. J. Haematol.?2001, 114, 271–280, doi:10.1046/j.1365-2141.2001.02908.x. 11529844
[2]
King, B.P.; Khan, T.I.; Aithal, G.P.; Kamali, F.; Daly, A.K. Upstream and coding region CYP2C9 polymorphisms: Correlation with warfarin dose and metabolism. Pharmacogenetics?2004, 14, 813–822, doi:10.1097/00008571-200412000-00004. 15608560
[3]
Gage, B.F.; Lesko, L.J. Pharmacogenetics of warfarin: Regulatory, scientific, and clinical issues. J. Thromb. Thrombolysis?2008, 25, 45–51, doi:10.1007/s11239-007-0104-y. 17906972
[4]
Palareti, G.; Leali, N.; Coccheri, S.; Poggi, M.; Manotti, C.; D’Angelo, A.; Pengo, V.; Erba, N.; Moia, M.; Ciavarella, N.; Devoto, G.; Berretini, M.; Musolesi, S. Hemorrhagic complications of oral anticoagulant therapy: Results of a prospective multicenter study ISCOAT (Italian Study on Complications of Oral Anticoagulant Therapy). G. Ital. Cardiol.?1997, 27, 231–243. 9244725
[5]
Hirsh, J.; Bates, S.M. Clinical trials that have influenced the treatment of venous thromboembolism: A historical perspective. Ann. Intern. Med.?2001, 134, 409–417. 11242501
[6]
Hirsh, J.; Dalen, J.; Anderson, D.R.; Poller, L.; Bussey, H.; Ansell, J.; Deykin, D. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest?2001, 119, 8S–21S, doi:10.1378/chest.119.1_suppl.8S. 11157640
[7]
Jones, D.R.; Kim, S.Y.; Guderyon, M.; Yun, C.H.; Moran, J.H.; Miller, G.P. Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin. Chem. Res. Toxicol.?2010, 23, 939–945, doi:10.1021/tx1000283. 20429590
[8]
Kamali, F.; Wynne, H. Pharmacogenetics of warfarin. Annu. Rev. Med.?2010, 61, 63–75, doi:10.1146/annurev.med.070808.170037. 19686083
[9]
Kaminsky, L.S.; Zhang, Z.Y. Human P450 metabolism of warfarin. Pharmacol. Ther.?1997, 73, 67–74, doi:10.1016/S0163-7258(96)00140-4. 9014207
[10]
Adcock, D.M.; Koftan, C.; Crisan, D.; Kiechle, F.L. Effect of polymorphisms in the cytochrome P450 CYP2C9 gene on warfarin anticoagulation. Arch. Pathol. Lab. Med.?2004, 128, 1360–1363. 15578879
[11]
Takahashi, H.; Echizen, H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin. Pharmacokinet.?2001, 40, 587–603, doi:10.2165/00003088-200140080-00003. 11523725
[12]
Rettie, A.E.; Wienkers, L.C.; Gonzalez, F.J.; Trager, W.F.; Korzekwa, K.R. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics?1994, 4, 39–42, doi:10.1097/00008571-199402000-00005. 8004131
[13]
Haining, R.L.; Hunter, A.P.; Veronese, M.E.; Trager, W.F.; Rettie, A.E. Allelic variants of human cytochrome P450 2C9: Baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch. Biochem. Biophys.?1996, 333, 447–458, doi:10.1006/abbi.1996.0414. 8809086
[14]
Steward, D.J.; Haining, R.L.; Henne, K.R.; Davis, G.; Rushmore, T.H.; Trager, W.F.; Rettie, A.E. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics?1997, 7, 361–367, doi:10.1097/00008571-199710000-00004. 9352571
[15]
Margaglione, M.; Colaizzo, D.; D’Andrea, G.; Brancaccio, V.; Ciampa, A.; Grandone, E.; Di Minno, G. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost.?2000, 84, 775–778. 11127854
[16]
Scordo, M.G.; Pengo, V.; Spina, E.; Dahl, M.L.; Gusella, M.; Padrini, R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin. Pharmacol. Ther.?2002, 72, 702–710, doi:10.1067/mcp.2002.129321. 12496751
[17]
Visser, L.E.; van Vliet, M.; van Schaik, R.H.; Kasbergen, A.A.; De Smet, P.A.; Vulto, A.G.; Hofman, A.; van Duijn, C.M.; Stricker, B.H. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics?2004, 14, 27–33, doi:10.1097/00008571-200401000-00003. 15128048
[18]
Wang, B.; Wang, J.; Huang, S.Q.; Su, H.H.; Zhou, S.F. Genetic Polymorphism of the Human Cytochrome P450 2C9 Gene and Its Clinical Significance. Curr. Drug. Metab.?2009, 10, 781–834, doi:10.2174/138920009789895480. 19925388
[19]
Furuya, H.; Fernandez-Salguero, P.; Gregory, W.; Taber, H.; Steward, A.; Gonzalez, F.J.; Idle, J.R. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics?1995, 5, 389–392, doi:10.1097/00008571-199512000-00008. 8747411
[20]
Aithal, G.P.; Day, C.P.; Kesteven, P.J.; Daly, A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet?1999, 353, 717–719, doi:10.1016/S0140-6736(98)04474-2. 10073515
[21]
Higashi, M.K.; Veenstra, D.L.; Kondo, L.M.; Wittkowsky, A.K.; Srinouanprachanh, S.L.; Farin, F.M.; Rettie, A.E. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA?2002, 287, 1690–1698, doi:10.1001/jama.287.13.1690. 11926893
[22]
Tabrizi, A.R.; Zehnbauer, B.A.; Borecki, I.B.; McGrath, S.D.; Buchman, T.G.; Freeman, B.D. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J. Am. Coll. Surg.?2002, 194, 267–273, doi:10.1016/S1072-7515(01)01163-2. 11893129
[23]
Taube, J.; Halsall, D.; Baglin, T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood?2000, 96, 1816–1819. 10961881
[24]
Wadelius, M.; Sorlin, K.; Wallerman, O.; Karlsson, J.; Yue, Q.Y.; Magnusson, P.K.; Wadelius, C.; Melhus, H. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J.?2004, 4, 40–48, doi:10.1038/sj.tpj.6500220. 14676821
Takahashi, H.; Echizen, H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J.?2003, 3, 202–214, doi:10.1038/sj.tpj.6500182. 12931134
[27]
London, S.J.; Daly, A.K.; Leathart, J.B.; Navidi, W.C.; Idle, J.R. Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. Pharmacogenetics?1996, 6, 527–533, doi:10.1097/00008571-199612000-00006. 9014202
[28]
Nasu, K.; Kubota, T.; Ishizaki, T. Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics?1997, 7, 405–409, doi:10.1097/00008571-199710000-00011. 9352578
[29]
Bhasker, C.R.; Miners, J.O.; Coulter, S.; Birkett, D.J. Allelic and functional variability of cytochrome P4502C9. Pharmacogenetics?1997, 7, 51–58, doi:10.1097/00008571-199702000-00007. 9110362
[30]
Schalekamp, T.; Klungel, O.H.; Souverein, P.C.; de Boer, A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch. Intern. Med.?2008, 168, 180–185, doi:10.1001/archinternmed.2007.32. 18227365
[31]
Dalton, S.O.; Sorensen, H.T.; Johansen, C. SSRIs and upper gastrointestinal bleeding: What is known and how should it influence prescribing? CNS Drugs?2006, 20, 143–151, doi:10.2165/00023210-200620020-00005. 16478289
[32]
Meijer, W.E.; Heerdink, E.R.; Leufkens, H.G.; Herings, R.M.; Egberts, A.C.; Nolen, W.A. Incidence and determinants of long-term use of antidepressants. Eur. J. Clin. Pharmacol.?2004, 60, 57–61, doi:10.1007/s00228-004-0726-3. 14985889
[33]
Greenblatt, D.J.; von Moltke, L.L.; Harmatz, J.S.; Shader, R.I. Drug interactions with newer antidepressants: Role of human cytochromes P450. J. Clin. Psychiatry?1998, 59 (Suppl. 15), 19–27. 9818627
[34]
DeVane, C.L. Differential pharmacology of newer antidepressants. J. Clin. Psychiatry?1998, 59 (Suppl. 20), 85–93, doi:10.4088/JCP.v59n0207f. 9881541
[35]
Hauta-Aho, M.; Tirkkonen, T.; Vahlberg, T.; Laine, K. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann. Med.?2009, 41, 619–628, doi:10.1080/07853890903186168. 19711211
[36]
Wallerstedt, S.M.; Gleerup, H.; Sundstrom, A.; Stigendal, L.; Ny, L. Risk of clinically relevant bleeding in warfarin-treated patients—influence of SSRI treatment. Pharmacoepidemiol. Drug Saf.?2009, 18, 412–416, doi:10.1002/pds.1737. 19301238
[37]
Wessinger, S.; Kaplan, M.; Choi, L.; Williams, M.; Lau, C.; Sharp, L.; Crowell, M.D.; Keshavarzian, A.; Jones, M.P. Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: A multicentre retrospective analysis. Aliment. Pharmacol. Ther.?2006, 23, 937–944, doi:10.1111/j.1365-2036.2006.02859.x. 16573796
[38]
Duncan, D.; Sayal, K.; McConnell, H.; Taylor, D. Antidepressant interactions with warfarin. Int. Clin. Psychopharmacol.?1998, 13, 87–94, doi:10.1097/00004850-199803000-00006. 9669190